Non-small Cell Lung Cancer

Background

• Non-small cell lung cancers are the most frequent (85%-90%) cause of malignant lung tumors, usually affecting adults who smoke and who are ≥ 65 years old.
• In 2018, there were 2,093,876 new cases of lung cancer worldwide, with annual age-standardized incidence 31.5 per 100,000 men and 14.6 per 100,000 women. Lung cancer was also the most common cause of cancer death, with annual age-standardized mortality 27.1 per 100,000 men and 11.2 per 100,000 women.
• Tobacco use is the main risk factor. Other risk factors include environmental exposures and genetic predisposition.
• Screening for lung cancer, with shared decision-making, is recommended for at-risk population persons.
  • Engage screening in persons aged 55-74 years with ≥ 30 pack-year history of smoking and smoking cessation < 15 years (Strong recommendation).
  • Consider engaging screening in persons aged ≥ 50 years with ≥ 20 pack-year history of smoking and additional risk factors (personal history of cancer or lung disease, family history of lung cancer, radon exposure, or relevant occupational exposure) that increases risk of lung cancer to ≥ 1.3% (not including second-hand smoke exposure) (Weak recommendation).
  • See Lung Cancer Screening for details.
• Strategies for prevention of lung cancer include smoking cessation and dietary intervention.

Evaluation

• Some common presenting symptoms include coughing, dyspnea, chest pain and hemoptysis. Up to 25% of lung cancers may be asymptomatic.
• Assessment for lung cancer should be performed by a multidisciplinary team, including thoracic surgeons, thoracic radiologists, and pulmonologists.
• For patients with suspected lung cancer based on history and physical examination, diagnosis is based on computed tomography (CT) with contrast of chest and upper abdomen, biopsy and pathology review, and blood tests (Strong recommendation).
• The first staging tests used should be the least invasive and safest method that will give the highest diagnostic yield; options include bronchoscopy with transbronchial needle aspiration (TBNA), endobronchial ultrasound-guided (EBUS) needle aspiration, endoscopic ultrasound-guided (EUS) needle aspiration, transthoracic needle aspiration, and mediastinoscopy.

Management

Management of Resectable Disease

• For patients with stage I and II resectable disease, if mediastinal nodes are negative on pretreatment evaluation (including minimally invasive nodal sampling) and patient can tolerate surgery, consider surgical resection plus mediastinal systematic sampling of lymph nodes or mediastinal lymph node dissection (Strong recommendation). Follow-up treatment options after resection depend on postsurgical stage and resection margins.
• For patients with clinical stage IIIA resectable disease:
  • For patients with clinical stage IIIA (T3, N1) and mediastinal nodes are negative on pretreatment evaluation (including minimally invasive nodal sampling), offer surgical exploration and resection plus systematic sampling of lymph nodes or mediastinal lymph node dissection (Strong recommendation). Follow-up treatment options after resection depend on postsurgical stage and resection margins.
  • For patients with clinical stage IIIA disease and T3 (invasion), N1, or T4 (extension), N0-N1
    • For superior sulcus tumor (T3 invasion, N1), consider neoadjuvant concurrent chemoradiation, followed by surgery and adjuvant chemotherapy (Weak recommendation)
    • For superior sulcus tumor (T4 extension, N0-N1) and tumor deemed possibly resectable, consider neoadjuvant concurrent chemoradiation followed by resection plus adjuvant chemotherapy if disease becomes resectable (Weak recommendation)
    • For disease in chest wall, proximal airway, or mediastinum (T3 invasion, N1, or resectable T4 extension, N0-N1), consider surgery alone as preferred initial treatment (Weak recommendation). Other option includes surgery preceded by neoadjuvant concurrent chemoradiation therapy or neoadjuvant chemotherapy (Weak recommendation).
  • For patients with clinical stage IIIA (T1-T2, N2) disease, treatment options depend on nodal status from mediastinal biopsy.
    • For resectable T1-T3 (including T3 with multiple nodules in same lobe), N0-N1 disease, consider surgical exploration and resection plus mediastinal lymph node dissection or systematic sampling (Weak recommendation), followed by adjuvant treatment based on postsurgical stage and resection margins.
    • For T1-T2 or T3 (other than invasive), N2 disease, initial treatment options include either
      • definitive concurrent chemoradiation, followed by durvalumab (Strong recommendation) (see Management of Unresectable Nonmetastatic Non-small Cell Lung Cancer for additional information);
      • induction chemotherapy with or without radiation therapy (Weak recommendation). Follow-up treatment options depend on disease progression.
        • If there is no apparent progression, consider surgery with or without adjuvant radiation therapy (if not previously given) , with or without adjuvant chemotherapy (Weak recommendation).
        • If there is local progression, consider radiation therapy (if not previously given) with or without chemotherapy (Weak recommendation).
        • If there is systemic progression, manage as advanced disease.
  • For patients with separate pulmonary nodules on same lobe (T3, N1) or on ipsilateral non-primary lobe (T4, N0-N1), consider initial treatment with surgery (Weak recommendation) followed by adjuvant treatment based on postsurgical stage and resection margins.

Management of Unresectable Nonmetastatic Disease

• For patients with stage I and II inoperable disease:
  • For patients with inoperable stage IA with negative mediastinal lymph nodes, consider definitive radiation therapy including stereotactic body radiation therapy (SBRT) (Weak recommendation).
  • For patients with inoperable stages IB-IIB with negative mediastinal lymph nodes (including minimally invasive nodal sampling):
    • If N0 disease after mediastinal node evaluation consider definitive radiation therapy, such as SBRT (Weak recommendation). For high-risk stages IB-IIB, consider follow-up treatment with chemotherapy after definitive radiation therapy (Weak recommendation).
    • If N1 disease after mediastinal node evaluation, consider definitive chemoradiation therapy (Weak recommendation) and follow with consolidation durvalumab (Strong recommendation).
    • If there is positive mediastinal lymph nodal involvement, manage as stage III disease.
• For most patients with unresectable clinical stage IIIA-IIIC disease (confirmed by minimally invasive nodal sampling), offer definitive concurrent chemoradiation therapy with platinum-based chemotherapy (Strong recommendation) and follow with consolidation durvalumab (Strong recommendation).

Management of Advanced Disease

• Offer early integrative palliative care, including discussion and shared decision-making with patient, family, and caregivers with regard to treatment goals, care planning, and quality of life considerations (Strong recommendation).
• First-line therapy depends on status of oncogenic driver mutations, PD-L1 expression, and histology.
• For patients with oncogenic driver mutations, offer first-line genotype-driven therapy. Complete or interrupt planned systemic therapy if the mutations are detected during first-line systemic therapy.
  • If a sensitizing EGFR mutation is detected, offer first-line EGFR-targeted therapy with any of the following: osimertinib, erlotinib, afatinib, gefitinib, dacomitinib (Strong recommendation).
  • If an ALK rearrangement is detected, offer first-line ALK-targeted therapy with any of the following: alectinib, brigatinib, ceritinib, or crizotinib (Strong recommendation); the preferred agent varies among guidelines.
  • If a ROS1 rearrangement is detected, offer first-line ROS1-targeted therapy with either crizotinib (Strong recommendation) or ceritinib (Weak recommendation).
  • If a BRAF V600E mutation is detected, offer first-line BRAF-targeted therapy with dabrafenib plus trametinib (Weak recommendation), or either vemurafenib alone or dabrafenib alone if the dabrafenib plus trametinib combination is not tolerated.
  • If a NTRK gene fusion is detected, larotrectinib is an option for first-line NTRK-targeted therapy (Weak recommendation).
• For patients with high PD-L1 expression (defined as tumor proportion score [TPS] ≥ 50%), offer single-agent pembrolizumab as preferred first-line therapy (Strong recommendation).
• For patients negative for oncogenic driver mutations and PD-L1 TPS < 50%, offer first-line systemic therapy.
  • For patients with nonsquamous histology:
    • If performance status is 0-1, offer platinum-based, pemetrexed-containing doublet chemotherapy in combination with pembrolizumab as the preferred option (Strong recommendation).
    • If performance status is 2, offer carboplatin-based doublet chemotherapy as the preferred option (Strong recommendation).
    • If performance status is 3-4, consider supportive care only (Weak recommendation).
  • For patients with squamous histology:
    • If performance status is 0-1, offer pembrolizumab plus carboplatin plus either paclitaxel or albumin-bound paclitaxel as the preferred option (Strong recommendation).
    • If performance status is 2, offer carboplatin-based doublet chemotherapy as the preferred option (Strong recommendation).
    • If performance status is 3-4, consider supportive care only (Weak recommendation).